Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTD7ZZ8)

• DOT Name: Diphthine methyltransferase (DPH7)
• Synonyms: EC 3.1.1.97; Diphthamide biosynthesis protein 7; WD repeat-containing protein 85
• Gene Name: DPH7
• Related Disease:
  Endometrial cancer
  Endometrial carcinoma
• UniProt ID: DPH7_HUMAN
• EC Number: 3.1.1.97
• Pfam ID: PF00400
• Sequence:
  MMGCFALQTVDTELTADSVEWCPLQGCRHLLACGTYQLRRPEDRPAGPQNKGGMEVKEPQ
  VRLGRLFLYSFNDNNSIHPLVEVQRKDTSAILDMKWCHIPVAGHALLGLADASGSIQLLR
  LVESEKSHVLEPLSSLALEEQCLALSLDWSTGKTGRAGDQPLKIISSDSTGQLHLLMVNE
  TRPRLQKVASWQAHQFEAWIAAFNYWHPEIVYSGGDDGLLRGWDTRVPGKFLFTSKRHTM
  GVCSIQSSPHREHILATGSYDEHILLWDTRNMKQPLADTPVQGGVWRIKWHPFHHHLLLA
  ACMHSGFKILNCQKAMEERQEATVLTSHTLPDSLVYGADWSWLLFRSLQRAPSWSFPSNL
  GTKTADLKGASELPTPCHECREDNDGEGHARPQSGMKPLTEGMRKNGTWLQATAATTRDC
  GVNPEEADSAFSLLATCSFYDHALHLWEWEGN
• Function: Catalyzes the demethylation of diphthine methyl ester to form diphthine, an intermediate diphthamide biosynthesis, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2) which can be ADP-ribosylated by diphtheria toxin and by Pseudomonas exotoxin A (Eta).
• Reactome Pathway: Synthesis of diphthamide-EEF2 (R-HSA-5358493)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[1]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[1]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Diphthine methyltransferase (DPH7).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diphthine methyltransferase (DPH7).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diphthine methyltransferase (DPH7).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Diphthine methyltransferase (DPH7).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Diphthine methyltransferase (DPH7).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Diphthine methyltransferase (DPH7).	[9]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Diphthine methyltransferase (DPH7).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Diphthine methyltransferase (DPH7).	[8]

References

• [1] Identification of new fusion genes and their clinical significance in endometrial cancer.Chin Med J (Engl). 2019 Jun 5;132(11):1314-1321. doi: 10.1097/CM9.0000000000000203.
• [2] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.